Impaired myocardial perfusion triggers inflammatory and angiogenic responses; enhancing angiogenesis is an emerging theme for the revascularization of ischemic myocardium. The interdependence of these processes is illustrated by the observation that inflammation is essential for the induction and maintenance of pathologic angiogenesis where angiogenic growth factors recruit inflammatory cells to myocardial sites of angiogenesis. Induction of both VEGF and the CD13/APN angiogenic regulator by the inflammatory mediator CD154 in endothelial cells establishes an essential link between inflammation and angiogenesis. CD13/APN expression is induced in the angiogenic peri-infarct zone after myocardial infarction where it co-localizes with CD154, thus indicating that myocardial angiogenesis relies on both processes. VEGF and PlGF (placental growth factor) form synergistically active heterodimers that also induce CD13/APN expression. These data invoke a molecular mechanism linking inflammation to expression of both early (PlGF, VEGF) and late (CD13/APN) angiogenic regulators. We hypothesize that the inflammatory mediator CD154 induces CD13/APN expression via a VEGF and PlGF-dependent mechanism, thereby stimulating angiogenesis in regions of myocardial ischemia. The goal of these studies is to elucidate the molecular mechanisms linking inflammatory cell signals to the induction, progression, and maintenance of angiogenesis in myocardial ischemia. We will determine the signaling and transcriptional mechanisms of CD13/APN induction by CD154 in primary endothelial cells in vitro. The contribution of components of the CD154- CD13/APN pathway to angiogenesis and wound healing after myocardial infarction and ischemia/reperfusion injury will be evaluated in murine models of myocardial disease in genetically modified animals in vivo. Elucidation of the molecular mechanisms responsible for the inflammatory regulation of angiogenesis will provide new mechanistic insights into myocardial angiogenesis and a basis for more rational approaches to treating ischemic cardiovascular disease.